M. T. Bianchi and E. J. Botzolakis contributed equally to the work. This paper has online supplemental material.
Microscopic kinetic determinants of macroscopic currents: insights from coupling and uncoupling of GABAA receptor desensitization and deactivation
Article first published online: 31 OCT 2007
The Journal of Physiology
Volume 584, Issue 3, pages 769–787, November 2007
How to Cite
Bianchi, M. T., Botzolakis, E. J., Haas, K. F., Fisher, J. L. and Macdonald, R. L. (2007), Microscopic kinetic determinants of macroscopic currents: insights from coupling and uncoupling of GABAA receptor desensitization and deactivation. The Journal of Physiology, 584: 769–787. doi: 10.1113/jphysiol.2007.142364
- Issue published online: 31 OCT 2007
- Article first published online: 31 OCT 2007
- (Resubmitted 2 August 2007; accepted after revision 31 August 2007; first published online 20 September 2007)
The time course of inhibitory postsynaptic currents (IPSCs) reflects GABAA receptor deactivation, the process of current relaxation following transient activation. Fast desensitization has been demonstrated to prolong deactivation, and these processes have been described as being ‘coupled’. However, the relationship between desensitization and deactivation remains poorly understood. We investigated the ‘uncoupling’ of GABAA receptor macroscopic desensitization and deactivation using experimental conditions that affected these two processes differently. Changing agonist affinity preferentially altered deactivation, changing agonist concentration preferentially altered macroscopic desensitization, and a pore domain mutation prolonged deactivation despite blocking fast desensitization. To gain insight into the mechanistic basis for coupling and uncoupling, simulations were used to systematically evaluate the interplay between agonist affinity, gating efficacy, and desensitized state stability in shaping macroscopic desensitization and deactivation. We found that the influence of individual kinetic transitions on macroscopic currents depended not only on model connectivity, but also on the relationship among transitions within a given model. In addition, changing single rate constants differentially affected macroscopic desensitization and deactivation, thus providing parsimonious kinetic explanations for experimentally observed uncoupling. Finally, these findings permitted development of an algorithmic framework for kinetic interpretation of experimental manipulations that alter macroscopic current properties.